Lipase-catalyzed kinetic resolution

Lipase-catalyzed kinetic resolutions are often practical for the preparation of optically active pharmaceuticals (61). For example, suprofen [40828-46-4] (45), which is a nonsteroidal antiinflamatory dmg, can be resolved by Candida glindracea]i 2Lse in >95% ee at 49% conversion (61). Moreover, hpase-based processes for the resolution of naproxen [22204-53-1] and ibuprofen [15687-27-1] (61) have also been developed. 

Figure 6.42 Lipase-catalyzed kinetic resolution of a p-lactam.

The outstanding influence of the anionic component on the activity and selectivity of enzymes was demonstrated in the Candida rugosa lipase-catalyzed kinetic resolution of ibuprofen, a nonsteroidal antiinflammatory drug with sales of USD 183 million in 2006 (Scheme 5.15) [63]. 

FINDING OF THE LOW-TEMPERATURE METHOD IN THE LIPASE-CATALYZED KINETIC RESOLUTION... 

Temperature effect in the lipase-catalyzed kinetic resolution of solketal... 

In a very new example, the Kita group has presented a neat combination of a lipase-catalyzed kinetic resolution of a-hydroxynitrones and a 1,3-dipolar cycloaddition, which was successfully applied in the asymmetric total synthesis of (-)-ros-marinecine [25]. 

For the syntheses of a large number of deoxypolypropionates requiring a,o -diheterofunctional intermediates, a couple of novel protocols, that are complementary with the conventional protocol using so-called Roche ester, have been developed (Scheme 33).199,200 More recently, the combined use of the ZACA reaction and the lipase-catalyzed kinetic resolution via selective acetylation has been shown to be practically attractive for the synthesis of enantio-merically pure compounds that cannot be readily purified by ordinary chromatography or recrystallization199,201 (Scheme 34). 

Scheme 34 ZACA-lipase-catalyzed kinetic resolution tandem protocol.

Inagaki, M. Hiratake, J. Nishioka, T Oda, J. One-pot synthesis of optically active cyanohydrin acetates from aldehydes via lipase-catalyzed kinetic resolution coupled with in situ formation and racemization of cyanohydrins. J. Org. Chem. 1992, 57, 5643-5649. 

Performing a systematic comparison of lipase-catalyzed kinetic resolutions of several seeondaiy aleohols in continuous flow mode (Figure 7) and shake flask batch mode using immobilized and non-mobilized lipases was reported by Csajagi and eo-workers [25]. The results indieated that immobilized as well as lyophilized powder forms of liphases can be effeetively used in eontinuous flow mode kinetie resolutions of raeemic alcohols in non-aqueous solvent systems. The produetivity of the lipases was higher in continuous flow reactors than in batch mode systems, whereas the enantiomer selectivities were similar. 

Lipase Catalyzed Kinetic Resolution of Alcohols via Chloroacetate Esters (-)-(lR,2S)-trans-2-Phenylcyclohexano1 and (+)-(lS,2R)-trans-2-Phenyl cyclohexanol... 

Another method for assaying the activity and stereoselectivity of enzymes at in vitro concentrations is based on surface-enhanced resonance Raman scattering (SERRS) using silver nanoparticles (116). Turnover of a substrate leads to the release of a surface targeting dye, which is detected by SERRS. In a model study, lipase-catalyzed kinetic resolution of a dye-labeled chiral ester was investigated. It is currently unclear how precise the method is when identifying mutants which lead to E values higher than 10. The assay appears to be well suited as a pre-test for activity. 

Similarly, lipase-catalyzed kinetic resolution has also been applied to intermediate nitrile alcohol 46 (Scheme 14.14). Best results were obtained by using immobilized Pseudomonas cepacia (PS-D) in diisopropyl ether, leading to excellent yield and enantiomeric excess of the desired (5)-alcohol 46a, along with (/J)-nitrile ester 47. Reduction of 46a with borane-dimethylsulhde complex, followed by conversion to the corresponding carbamate and subsequent lithium aluminum hydride reduction gave rise to the desired (S)-aminoalcohol intermediate 36, a known precursor of duloxetine (3). 

A series of flavan-4-ols, e.g., 108, was conveniently prepared by metal hydride reduction of the corresponding flavanone. The flavan-4-ols were converted into the 4-methoxyflavans, e.g., 109, by acid-catalyzed solvolysis in methanol. Both these classes of compounds are currently evaluated as anticancer drugs. Enantiomerically enriched cA-flavan-4-ols have been prepared by lipase-catalyzed kinetic resolution of racemic counterparts. ... 

Todoroki, T., Saito, A., and Tanaka, A., Lipase-catalyzed kinetic resolution of ( )-cw-flavan-4-ol and its acetate synthesis of chiral 3-hydroxyflavanones, Bioscl Biotechnol Biochem., 66, 1172, 2002. 

Conventional gas chromatography (GC) based on the use of chiral stationary phases can handle only a few dozen ee determinations per day. In some instances GC can be modified so that, in optimal situations, about 700 exact ee and E determinations are possible per day [29]. Such meclium-throughputmay suffice in certain applications. The example concerns the lipase-catalyzed kinetic resolution of the chiral alcohol (R)- and (S)-18 with formation of the acylated forms (R)- and (S )-19. Thousands of mutants of the lipase from Pseudomonas aeruginosa were created by error-prone PCR for use as catalysts in the model reaction and were then screened for enantioselectivity [29]. 

LIPASE-CATALYZED KINETIC RESOLUTION OF ALCOHOLS VIA CHLOROACETATE ESTERS (-)-(1R,2S)-trans-2-PHENYLCYCLOHEXANOL AND (+)-(1S,2R)-trans-2-PHENYLCYCLOHEXANOL... 

Rosen TC, Haufe G (2002) Synthesis of enantiopure monofluorinated phenylcyclopropanes by lipase-catalyzed kinetic resolution. Tetrahedron Asymmetry 13 1397-1405... 

LIPASE-CATALYZED KINETIC RESOLUTION OF RACEMATES A VERSATILE METHOD FOR THE SEPARATION OF ENANTIOMERS... 

Resolution of racemates via lipase-catalyzed kinetic resolution is one of the most attractive methods used to access to enantiomerically pure compounds. Of all methods used in kinetic resolution, transesterification in organic solvents catalyzed by lipase is the most dominant one. Thus, in the presence of a suitable acyl donor, an enzyme as well as the appropriate solvent, and at the optimum temperature, one enantiomer of the racemic mixture is selectively transferred to the corresponding ester leaving the second unreacted enantiomer in enantiomerically pure form.51-58... 

Racemic l-azido-3-aryloxy-2-propanols 35 was resolved by the lipase-catalyzed kinetic resolution using different acyl donors to access to the enantiomers in optically pure form.66 The reduction of the azide group can afford the l-amino-3-aryloxy-2-propanols, which is present in numerous biologically active compounds such as [3-adrenolytic drugs (/ -blockers) used in the treatment of angina pectoris, hypertension and other cardiac diseases. 

Figure 43 Lipase-catalyzed kinetic resolution of (ram -2-(ter(-butyldimethylsiloxymethyl) cyclopentanol (rac-82).86...

Figure 44 Lipase-catalyzed kinetic resolution of (i ,5)-3-(4-methoxyphenoxy)propane-l,2-diol (rac-84).

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